Substantial interest in harnessing the immune system as a means of therapy for cancer has arisen from both animal and human subject studies. These studies have revealed the potential benefits of triggering specific immune components, including T lymphocytes, against cancer. The success of these therapies requires a well-coordinated series of physical and biochemical events, mediated by various immune cells and cytokines. In addition, it is now widely accepted that the immune system is also subject to regulation by neuroendocrine- derived products that are associated with psychological stress, an important concern for diseases such as cancer which are associated with a high degree of anxiety. However, there is a general lack of information regarding the impact of psychological stress on T cell-based immune defenses against cancer and the neuroendocrine and immunological mechanisms that are involved. To address this issue, well-established murine models of stress-induced neuroendocrine activation and CD8+ T cell-mediated immunity to oncogene- derived tumors will be merged to embark upon a new and previously unexplored area in the field of psychoneuroimmunology. The broad objective of this R21 application is to determine the extent to which psychological stress modulates the immune response against cancer. The proposed studies will test the hypothesis that acute and/or chronic psychological stress modulates the CD8+ T cell response to a well- characterized epitope within the SV40 large T antigen oncogenic protein in transgenic mice that develop spontaneous tumors. We will investigate mechanisms by which psychological stress modulates T cell activation, differentiation and survival following recognition of the endogenous tumor antigen or an immunotherapeutic vaccine. In addition, we will assess potential mechanisms that modulate T cell accumulation within established tumors as well as T cell effector function and control of tumor progression. The rationale for the proposed research is based on the fact that a role for stress in the development and progression of cancer has been suggested and, in some cases, demonstrated, but that the precise role of the neuroendocrine-immune relationship in cancer and the mechanisms involved are not known. At the completion of this project we will expect to have broadly defined the impact of psychological stress on CD8+ T cell-based immunity to cancer and be in a strong position to design additional studies to precisely define the neuroendocrine and immunological mechanisms that can influence immunotherapeutic approaches for cancer. The studies described in this proposal provide a foundation for determining the impact of psychological stress on immune-mediated defense against cancer. An understanding of the relationship among stress, immunotherapy, and cancer will determine how patients with cancer are treated from not only a pharmacological but also a psychological perspective.